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Translational Therapeutics

Therapeutic silencing of mTOR by systemically administered siRNA-loaded neutral liposomal nanoparticles inhibits DMBA-induced mammary carcinogenesis

British Journal of Cancer volume 127, pages 2207–2219 (2022)Cite this article

Subjects

Abstract

Background

Mammary carcinogenesis possesses great challenges due to the lack of effectiveness of the multiple therapeutic options available. Gene therapy-based cancer treatment strategy provides more targeting accuracy, fewer side effects, and higher therapeutic efficiency. Downregulation of the oncogene mTOR by mTOR-siRNA is an encouraging approach to reduce cancer progression. However, its employment as means of therapeutic strategy has been restricted due to the unavailability of a suitable delivery system.

Methods

A suitable nanocarrier system made up of 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) has been developed to prevent degradation and for proficient delivery of siRNA. This was followed by in vitro and in vivo anti-breast cancer efficiency analysis of the mTOR siRNA-loaded neutral liposomal formulation (NL-mTOR-siRNA).

Results

In our experiment, a profound reduction in MCF-7 cell growth, proliferation and invasion was ascertained following extensive downregulation of mTOR expression. NL-mTOR-siRNA suppressed tumour growth and restored morphological alterations of DMBA-induced breast cancer. In addition, neutral liposome enhanced accumulation of siRNA in mammary cancer tissues facilitating its deep cytosolic distribution within the tumour, which allows apoptosis thereby facilitating its anti-tumour potential.

Conclusion

Hence, the current study highlighted the augmented ground for therapies aiming toward cancerous cells to diminish mTOR expression by RNAi in managing mammary carcinoma.

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Fig. 1: Morphological characterisation of DOPC-based neutral nanoliposome.
Fig. 2: Haemolysis assay and cellular uptake analysis of neutral nanoliposome.
Fig. 3: In vitro activity of mTOR siRNA-loaded neutral liposome.
Fig. 4: In vivo uptake of siRNA-loaded neutral liposome into the tumour tissue.
Fig. 5: In vivo anti-tumour efficacy of mTOR siRNA-loaded neutral liposome in DMBA-induced breast tumour model in SD rats.
Fig. 6: In vivo mTOR downregulation following NL-mTOR-siRNA administration.
Fig. 7: Induction of apoptosis in DMBA-induced mammary tumours by mTOR siRNA-loaded neutral liposome.
Fig. 8: Histopathological analysis of rats treated with or without mTOR siRNA-loaded neutral liposome.

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Acknowledgements

We acknowledge the support provided by the Central Instrumentation facility (CIF), Birla Institute of Technology, Mesra, Ranchi and HR-TEM facility of Vellore Institute of Technology in the characterisation of liposomal preparation.

Funding

This study was supported by Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi, India. This work has been funded by UGC (201819-NFO-2018-19-OBC-ORI-80495).

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Author notes

  1. These authors contributed equally: Roja Sahu, Shakti Prasad Pattanayak.

Authors and Affiliations

  1. Division of Advanced Pharmacology, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835 215, India

    Roja Sahu

  2. Division of Pharmacognosy and Phytochemistry, Department of Pharmaceutical Sciences & Technology, Birla Institute of Technology (BIT), Mesra, Ranchi, Jharkhand, 835 215, India

    Shivesh Jha

  3. Department of Pharmacy, School of Health Science, Central University of South Bihar (Gaya), Gaya, Bihar, 824 236, India

    Shakti Prasad Pattanayak

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Contributions

RS and SPP conducted the experiments and wrote the manuscript with equal contribution. SPP and RS was responsible for confocal microscopy, Western blot, immunohistochemistry and flow cytometry. RS and SJ took part in the in vivo experiments. SJ analysed the data and revised the manuscript. SPP designed the research plan, analysed the data and revised the manuscript. All authors have approved the manuscript.

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Correspondence to Shakti Prasad Pattanayak.

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This animal study was approved by the Institutional Animal Ethical Committee, Birla Institute of Technology, Mesra, Ranchi (approval no. 1972/PH/BIT/113/20/IAEC). All animal experiments were conducted in accordance with the Institutional Animal Ethical Committee (IAEC) regulation. This study did not include patient participation or analysis of patient data.

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Sahu, R., Jha, S. & Pattanayak, S.P. Therapeutic silencing of mTOR by systemically administered siRNA-loaded neutral liposomal nanoparticles inhibits DMBA-induced mammary carcinogenesis. Br J Cancer 127, 2207–2219 (2022). https://doi.org/10.1038/s41416-022-02011-1

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